For the treatment of a wide variety of different nervous and mental diseases, it is desirable to be able to monitor the effectiveness of drugs and substances which affect brain chemistry. For instance, in the treatment of schizophrenia or Parkinson's Disease, it is highly desirable to be able to gauge the biochemical effects of drugs administered for blocking the patient's dopamine receptors. If too little of the drug is administered, the desired blockade does not occur, and if too much of the drug is administered, there can be severe side effects.
New and powerful imaging methods which enable one to assess the living brain in vivo and thereby monitor the effectiveness of drugs and substances that affect brain chemistry have recently been developed. Methods such as positron emission tomography (PET) and single photon emission tomography (SPECT) involve the administration to a patient of radioactive tracer substances comprising a ligand that binds to presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays which are emitted from the positrons or photons emitted from the radioactive tracer) are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or inter-person control, to determine the degree of drug response. Further treatment of the patient with drugs is based upon the comparisons made.
It is generally accepted that there are two subtypes of dopamine receptors, designated as D-1 and D-2 receptors. Recent reports have suggested that these two subtypes of receptors exhibit opposite biochemical effects: D-1 agonists stimulate adenyl cyclase activity, while D-2 agonists inhibit the enzyme activity. It is clear that these receptor subtypes influence each other, and yet they display separate and distinct functions on body physiology and biochemistry. Monitoring of both D-1 and D-2 receptors in a patient is important for assessing the dopaminergic system and ultimately assisting patient management.
Numerous benzazepine derivatives which are D-1 receptors have been disclosed. Examples are provided below in Table I.
TABLE I ______________________________________ Dopamine D-1 Receptors ##STR1## Compound R.sub.1 R.sub.2 R.sub.3 ______________________________________ SCH-23390 Cl H H SKF-83566 Br H H SCH-23982 I H H IMAB Cl N.sub.3 I FISCH Cl I H ______________________________________
For more detail, see the disclosure of U.S. Pat. No. 5,068,326 to Kung, the disclosure of which is hereby incorporated by reference; Chumpradit, S. et al., J. Med. Chem. 34, No. 3, 877-883 (1991); and Billings, J. J. et al., J. Neurochem 58, No. 1, 227-236 (1992).
There are also many known examples of dopamine D-2 receptors, such as those illustrated below in Table II.
TABLE II ______________________________________ Dopamine D-2 Receptors ______________________________________ ##STR2## Raclopride (K.sub.d 10 nM) ##STR3## IBZM (K.sub.d 0.426 nM) ##STR4## IBF (K.sub.d 0.106 nM) ##STR5## Fluoropropyl- Epidepride (K.sub.d 0.03 nM) ##STR6## Epidepride (K.sub.d 0.024 nM) ##STR7## Ioxipride (K.sub.d 0.019 nM) NCQ298 ______________________________________
For further discussion of these and related D-2 receptors, see the following: European Patent Application No. 393,838, published Oct. 24, 1990, and equivalent to allowed U.S. patent application Ser. No. 339,006, filed Apr. 17, 1989, the disclosure of which is hereby incorporated by reference; Hogberg, T., et al., Acta Pharm. Suec. 24, 289-328 (1987); Halldin, C., et al., Nucl. Med. Biol. 18, No. 8, 871-881 (1991); Hogberg, T. et al., J. Med. Chem. 34, 948-955 (1991); De Paulis, T., et al., Helvetica Chimica Acta 74, 241-254 (1991); Yue, E. W. et al., J. Org. Chem. 56, 5451-5456 (1991); Kessler, R. M. et al., J. Nucl. Med. 32, No. 8, 1593-1600 (1991); Murphy, R. A., et al., J. Med. Chem. 33, No. 1, 171-178 (1990); Kung, H. F., et al., Seminars in Nuclear Medicine, Vol. XX, No. 4, 290-302 (1990); Kung, H. F. et al., J. Nucl. Med. 30, No. 1, 88-92 (1989); Kung, H. F. et al., J. Nucl. Med. 31, 573-579 (1990); Kung, M-P. et al., J. Nucl. Med. 31, 648-654 (1990); Kung, M-P. et al., J. Nucl. Med. 32, 339-342 (1991); European Patent Application 60,235, published Jan. 8, 1986; European Patent Application 156,776, published Oct. 2, 1985; European Patent Application 207,913, published Jan. 7, 1987; PCT Patent Application PCT/GB84/00047 published under publication number WO 84/03281 on Aug. 30, 1984; and European Patent Application 234,872, published Sep. 2, 1987.
In general, it is well recognized that of the two imaging methods, PET and SPECT, PET provides higher resolution, higher sensitivity and better quantitation capability. SPECT imaging, however, offers the advantages of being more readily available, cheaper to perform and of being technically less demanding as it can be performed without the need of an on-site cyclotron. Currently, different dopamine receptor-specific imaging agents are used for PET and SPECT imaging, so data obtained for PET cannot be easily transferred to SPECT, and vice versa. In many cases, the different agents are close analogs, but they are not the same molecule, and pharmacokinetic and metabolic differences prevent their cross comparison. It would therefore be of great use to bridge the gap and to provide a single radiopharmaceutical for both PET and SPECT imaging.